1. Field of the Invention
The present invention generally relates to a novel one step halogenation/amination synthesis for producing phenothiazinium compounds from phenothiazine.
2. Discussion of the Background Art
There has been recent advances in the use of compounds having a photosensitizing chromophoric system, a sulphonamido functionality and a carboxy functionality as a photosensitizer in photodynamic therapy (PDT), in photochemical internalization in the production of a cancer vaccine or in the diagnosis or detection of medical conditions.
These photosensitizing chromophoric systems are preferably residue of a metal-free phthalocyanine, a methyl phthalocyanine, a benzoporphyrin, a purpurin, a chlorin, a bacteriochlorin, a tetraarylporphyrin, a porphycene or a texaphyrin, more preferably a residue of a metal phthalocyanine, a chlorin or a bacteriochlorin, especially a residue of a metal phthalocyanine, as set forth in US-2003/0180224, which is incorporated herein in its entirety.
Such phenothiazinium compounds are disclosed in WO-02/096896 as comprising the following formula (I):
wherein A and B are each independently selected from the group consisting of:
wherein Z is CH2, O, S, SO2, NH, NCH3, HC2H5, NCH2CH2OH or HCOCH3 and R1 and R2 are each independently linear or branched CnH2nY, where n is 1–6, Y is H, F, Cl, Br, I, OH, OCH3, OC2H5, OC3H7, CN or OCOCH3, and where Xp− is a counteranion and P is 1, 2 or 3.
Unfortunately, WO-02/096896 does not teach a commercially acceptable synthesis route for the manufacture of such phenothiazinium compounds, or any synthesis route for that matter.
K. J. Mellish et al. (Photochem. Photobiol., 2002, 75/4, 392–397) describes the synthesis of a series of tetraalkyl-iodide-derivatives of phenothiazine by an elaborate procedure. The phenothiazine is halogenated first and isolated, and then reacted at room temperature with the appropriate N,N-dialkylamine. The compounds are isolated by an elaborated work-up procedure using, e.g., halogenated solvents and only characterized by mass spectrometry. The purity cannot be derived from the data given.
N. Leventis et al. (Tetrahedron, 1997, 53/29, 10083–10092) describes the synthesis of a series of thiazine dyes. The synthesis is performed in two steps by halogenating phenothiazine in glacial acetic acid and then reaction with the corresponding amine in ethanol. The last step requires workup with chloroform and then isolation by column chromatography using chloroform/MeOH. The evaporation of the organic fractions is followed by recrystallization. This extensive procedure is not practicable for a large-scale synthesis.
L. Strekowski et al. (J. Heterocycl. Chem. 1993, 30/4, 1693–1695) describes the synthesis of dialkylamino-phenothiazin-derivatives with two different amino groups and I3− as the counterion. The compounds are synthesized in a two-step synthesis.
K. W. Loach (J. Chrom., 1971, 60, 119–129) describes the purification and analysis of a series of thiazine dyes. It concedes that in former literature “published procedures appear to give incomplete resolution of complex mixtures or separate them very slowly.” The paper describes only analytical separations, using mixtures of alcohol/chloroform/acetic acid which are disadvantageous because of the use of halogenated solvents and the mixture not being stable over more than 24 hours. Also, the separations had to be performed in the dark as the compounds showed significant photodecomposition. Also see U.S. Pat. No. 3,641,016 (Korosi et al.).
It would be desirable to develop a simple commercial synthesis for phenothiazinium compounds from phenothiazine.
The present invention preferably provides the following: an easy one-pot/one-step synthesis with crystallization right from the reaction mixture; eliminates the use of halogenated solvents and methanol during the reaction which also adds to process safety, as methanol/bromine mixtures are hazardous; eliminates the use of halogenated solvents and methanol in the workup; completely eliminates the need to use chromatography which is expensive, causes photodecomposition of material, requires the use of halogenated solvents and silica and causes inconsistent purity results; improves the yield using higher reaction temperature; and results in consistent, high purity yields which are reproducible.